Hepatocyte growth factor and HER2/neu downregulate expression of apoptosis-inducing factor in non-small cell lung cancer

Abstract

Abstract. Our previous study showed that patients with advanced stages of non-small cell lung cancer (NSCLC) were frequently detected with upregulation of hepatocyte growth factor (HGF). In vitro, HGF reduced expression of apoptosis-inducing factor (AIF) and cisplatin sensitivity in NSCLC cells. The effect of HGF was via HGF receptor (c-MET) and the downstream effector, focal adhesion kinase (FAK). In this study, we determined the prognostic value of AIF in NSCLC patients. AIF expression was determined by immunohistochemistry and immunoblotting. Our data show that AIF expression was associated with better prognosis. Expression of AIF inversely correlated with that of positive NSCLC markers, e.g., dihydrodiol dehydrogenase (DDH), c-MET, short oncostatin M receptor (OSMRs), matrix metalloproteinase (MMP)-1, and HER2/neu, which were closely associated with drug resistance, tumor recurrence, metastasis and poor prognosis. Noteworthy, silence of HER2/neu gene expression increases AIF level and drug sensitivity. Addition of HGF inhibits AIF expression in HER2/neu-silenced cells. These results suggested that both HGF and HER2/neu affect drug resistance by regulating AIF expression in NSCLC. IntroductionLung cancer is one of the leading causes of cancer death worldwide. In the United States, the annual mortality rate of lung cancer (estimated 180,000 deaths, male: 73.5/10 5 personyear; female: 41.5/10 5 person-year) is approximately 30% of total cancer-related deaths (1), and nearly 85-90% of lung cancer deaths are attributed to tobacco smoking (2). In Taiwan, the annual mortality rate of lung cancer is approximately 20% (estimated 6,000 deaths, male: 21/10 5 person-year; female: 10.3/10 5 person-year) (3). Lung carcinoma is categorized into small cell lung cancer (SCLC) or non-small cell lung cancer (NSCLC) with neuroendocrine features of the cancer cells. Based on the histopathological characteristics, NSCLC can be subcategorized into adenocarcinoma (ADC), squamous cell carcinoma and large cell carcinoma (4). Of note, among these, ADC, which is associated with a higher frequency of drug resistance and mortality than the other types, is most commonly found in women and smokers (5).Previous studies have indicated that tobacco smoking is a key risk factor for lung cancer (1,2,5,6). In patients with stage I NSCLC, we demonstrated that tobacco smoking and tumor size, but not visceral pleural invasion, are major factors influencing overall and disease-free survival (6). Moreover, accumulated evidence showed that NSCLC patients who continued to smoke were more resistant to chemotherapy and irradiation, and had poorer prognosis (6-9). Although nicotine per se is not directly associated with tumorigenesis, catalyzed nicotine is carcinogenic (10,11). In addition, nicotine induces NSCLC growth, and increases angiogenesis in tumors probably via activating nicotinic acetylcholine receptor (nAchR), epidermal growth factor receptor (EGFR) and .Using differential display alone or in combination with microarray, we previously identifi...

AIF inhibits tumor metastasis by protecting PTEN from oxidation

“…Also, two previous reports showed that there was higher AIF expression in the majority of gastric carcinoma 60 and colorectal carcinoma 61. The similar phenomena could also been found in our colorectal carcinoma cohort, although AIF expression was shown to be decreased in many other tumor types, contributing to their chemoresistance 2 62. Our unpublished data showed that hypoxia inhibits AIF expression, and low AIF expression mainly exists in hypoxic regions of cancer tissues, although most cancer tissues expressed higher AIF.…”

Regulation of metastatic ability and drug resistance in pulmonary adenocarcinoma by matrix rigidity via activating c-Met and EGFR

“…Vescular endothelial growth factor (VEGF) is a well known factor involved in cancer metastasis and growth, and inhibition of VEGF has been widely used in clinical cancer therapy [27]. For lung adenocarcinoma, inhibition of EGFR and c-Met signaling pathway are also therapeutic strategies [12,17,18]. We found that increase in matrix rigidity gradually upregulated the expression of c-Met (Fig.…”

“…Clinical research has revealed that the activation of signaling pathways by the epidermal growth factor receptor (EGFR) and hepatocyte growth factor (HGF) receptor (c-Met) is closely associated with the growth and metastasis of NSCLC, including pulmonary adenocarcinoma [12,17,18]. Therefore, the interaction between adenocarcinoma cells and extracellular matrices with different matrix rigidities is critical for identifying the underlying mechanism of poor prognosis in patients with pulmonary adenocarcinoma and lung fibrosis.…”

Recent Progress and Advances in HGF/MET-Targeted Therapeutic Agents for Cancer Treatment

“…It was found that expression level of AIF inversely correlated with the expression of positive NSCLC markers, such as dihydrodiol dehydrogenase (DDH), MET, short oncostatin M receptor (OSMR), matrix metalloproteinase (MMP)-1, and HER2/neu, which were closely associated with drug resistance, tumor recurrence, metastasis, and poor prognosis. Addition of HGF inhibited AIF expression level in HER2/neu-silenced cells, indicating that both HGF and HER2/neu affect drug resistance by regulating AIF expression level in NSCLC [105]. …”